Self-retaining sutures of poly-4-hydroxybutyrate and copolymers thereof

ABSTRACT

Methods for producing absorbable self-retaining sutures that have high tensile strengths and pronounced sheath-core structures wherein the sheath is harder than the core are also provided. The self-retaining sutures may be made by spinning and orienting a monofilament fiber of poly-4-hydroxybutyrate or copolymer thereof and inserting retainers in monofilament fibers.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims benefit of and priority to U.S. ProvisionalPatent Application No. 62/037,812 filed on Aug. 15, 2014, and isincorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention generally relates to self-retaining absorbablesutures of poly-4-hydroxybutyrate (P4HB) and copolymers thereof, withimproved straight pull tensile strengths.

BACKGROUND OF THE INVENTION

Self-retaining sutures have previously been developed for use in woundclosure, and other surgical procedures such as plastic surgery, see forexample US Patent Application No. 2005/0267532 to Wu. These suturescontain tissue retainers (e.g. barbs) placed in a variety of differentconfigurations along the suture fiber that when implanted project fromthe suture surface into tissue and resist movement in a directionopposite to the direction the tissue retainer faces.

The process of cutting tissue retainers into suture fiber decreases thecross-section of fiber that can support a load, and therefore cuttingtissue retainers into a suture fiber decreases the straight pull tensilestrength of the suture fiber. The straight pull tensile strength of aself-retaining suture is very important for several reasons. First,during implantation of the suture, force is applied along the axis ofthe suture fiber. The straight pull tensile strength of theself-retaining suture must be sufficient to prevent breakage of thesuture during implantation. Second, immediately after placement, thesuture must be strong enough to resist forces applied by the body, andparticularly by strong muscles. For example, if the self-retainingsuture is used in the face, the suture must be strong enough to resistforces applied by the patient when smiling, laughing, eating, frowning,etc. Third, if the self-retaining suture is absorbable it is vital thatcutting tissue retainers in the suture does not decrease the strengthretention profile so that it is too short to allow replacement of thesuture's load carrying capacity by the body. For example, there shouldbe enough time for the body to generate sufficient fibrotic tissue andadequate support before there is a critical loss of the suture's tensilestrength (including the strength exerted by the tissue retainers).

Unfortunately, commercially available self-retaining absorbable suturesdo not meet the US Pharmacopeia standard for average minimum knot-pullstrength (measured by straight pull). For example, to meet the USPtensile strength for an absorbable suture of size 3-0, a surgeon mustnot only use a size 2-0 of Quill's Monoderm (a copolymer of glycolideand ε-caprolactone) self-retaining suture (see Angiotech product packageinsert P/N 03-5296R2), but the size 2-0 Quill Monoderm self-retainingsuture also must have an oversized diameter. The size overage may be anincrease in suture diameter of up to 0.1 mm. So, it is necessary notonly to use a suture that is one size larger on the USP standards scale,but that is also oversized by up to 0.1 mm in diameter. Another exampleis Quill's PDO (polydioxanone) self-retaining sutures. To meet, forexample, the USP tensile strength of a size 3-0 suture, a surgeon mustnot only use a size 2-0 of Quill's PDO (polydioxanone) self-retainingsuture (see Angiotech product package insert P/N 03-5278R3), but alsothe size 2-0 suture must also be oversized in diameter by up to 0.1 mm.Greenberg, J. A. The use of barbed sutures in obstetrics and gynecology,Rev. Obstet. Gynecol. 3(3):82-91 (2010) also states clearly “Owing toits decreased effective diameter as a result of the process of creatingbarbs, barbed suture is typically rated equivalent to 1 USP suture sizegreater than its conventional equivalent. For example, a 2-0 barbedsuture equals a 3-0 smooth suture”. Consequently, surgeons are currentlyrequired to use suture diameters much larger than desired in order forthe strength to be adequate for the repair, create suture tunnels intissue that are larger than necessary, and in certain cases use suturesthat are less pliable than might be desired.

Thus, in the practice of surgery there currently exists a need forabsorbable self-retaining sutures with tensile strengths that meet orapproximate (i.e. do not stray too far from) the standards of the USPharmacopeia. These sutures would allow the surgeon to use smallerdiameter sutures than is currently possible without compromising thetensile strength of the suture. The use of these absorbableself-retaining sutures would also decrease the amount of foreignmaterial that needs to be implanted in the body, decrease the size ofsuture tunnels in a patient's tissues, and also provide more pliablesuture options.

It is therefore an object of this invention to provide absorbablemonofilament fibers and self-retaining sutures with high tensilestrengths.

It is a further object of this invention to provide absorbableself-retaining sutures with smaller diameters and high tensilestrengths.

It is yet a further object of this invention to provide absorbableself-retaining sutures with straight pull tensile strengths that equalor exceed the average minimum knot-pull tensile standards set by theUnited States Pharmacopeia (USP) wherein the self-retaining sutures arenot oversized more than 0.1 mm in diameter.

It is still a further object of this invention to provide absorbableself-retaining sutures with high tensile strengths that are alsopliable.

It is yet another object of this invention to provide methods to produceabsorbable self-retaining sutures that have high tensile strengths.

It is still yet another object of this invention to provide methods toproduce fibers of P4HB and copolymers thereof that have pronouncedsheath-core structures wherein the sheath is harder than the core.

It is even yet another object of this invention to provide methods toimplant absorbable self-retaining sutures that have high tensilestrengths.

SUMMARY OF THE INVENTION

Absorbable monofilament fibers and self-retaining sutures with hightensile strengths have been developed. The straight pull tensilestrengths of the absorbable self-retaining sutures closely approximate,equal or exceed the average minimum knot-pull tensile standards set bythe United States Pharmacopeia (USP). In one embodiment, the sutures aremade from poly-4-hydroxybutyrate or copolymers thereof.

The monofilament fibers of P4HB and copolymers have USP suture sizesranging from size 4 to size 6-0 and Young's Modulus values that arepreferably greater than 860 MPa, more preferably greater than 900 MPa,and even more preferably greater than 1 GPa. The diameters of themonofilament fibers of P4HB and copolymers may range from 0.05 mm to 1mm, but are more preferably 0.07 mm to 0.799 mm, equivalent to USPsuture size 6-0 to USP suture size 4 and oversized by up to 0.1 mm.

The straight pull tensile strengths of the monofilament fibers of P4HBand copolymers allow these fibers to be converted in some embodiments toself-retaining sutures with the following minimum straight pull tensilestrengths: (i) 0.25 Kgf for a USP size 6-0 self-retaining suture; (ii)0.68 Kgf for a USP size 5-0 self-retaining suture; (iii) 0.95 Kgf for aUSP size 4-0 self-retaining suture; (iv) 1.77 Kgf for a USP size 3-0self-retaining suture; (v) 2.68 Kgf for a USP size 2-0 self-retainingsuture; (vi) 3.9 Kgf for a USP size 0 self-retaining suture; (vii) 5.08Kgf for a USP size 1 self-retaining suture; (viii) 6.35 Kgf for a USPsize 2 self-retaining suture; and (ix) 7.29 Kgf for a USP size 3 or 4self-retaining suture.

Methods for producing monofilament fibers with high tensile strengths,hard surfaces and pronounced sheath-core structures are provided. In onepreferred embodiment, these monofilaments are prepared by fiber spinningIn a particularly preferred embodiment, the monofilament fibers used tomake the high tensile strength self-retaining sutures are made by meltextrusion. The P4HB monofilament fibers may be prepared by: (i) dryingbulk P4HB resin in pellet form until it has a water content of less than300 ppm using a rotary vane vacuum pump system, (ii) transferring thedried pellets to the feed hopper of the extruder fitted with a drynitrogen purge to keep the pellets dry, (iii) gravity feeding the P4HBpellets into a chilled feeder section, introducing the pellets into theextruder barrel, feeding the heated and softened resin into a heatedmetering pump (melt pump), and from the metering pump feeding the resininto a heated block and an eight-hole spinneret assembly, using aprocessing profile of 40° C. to 260° C. for temperatures, and 400 psi to2,000 psi for pressures, (iv) water quenching the molten P4HBmonofilaments, and (v) conveying the quenched filaments into amulti-stage orientation line, and stretching of at least 6×, beforewinding the high strength P4HB monofilament fiber on spools. Fibers withincreased surface hardness values may be obtained by increasing the drawratio during orientation of the fibers of P4HB and copolymers thereof.The draw ratio is preferably at least 6×, more preferably at least 6.5×,and even more preferably at least 7×. In a particularly preferredembodiment the draw ratio is 7.2× or more.

Methods for producing absorbable self-retaining sutures that have hightensile strengths and pronounced sheath-core structures wherein thesheath is harder than the core are also provided. The self-retainingsutures may be made by spinning and orienting a monofilament fiber ofpoly-4-hydroxybutyrate or copolymer thereof which has an average surfaceindentation hardness at least 0.07 GPa and inserting retainers inmonofilament fibers. In one embodiment, the retainer-forming stepincludes cutting the high tensile strength absorbable monofilament fiberwith a cutting element positioned at a desired angle relative to thelongitudinal axis of the monofilament. In this embodiment, the angle ofthe cut forming the retainer measured relative to the longitudinal axisof the fiber is less than 90 degrees, more preferably less than 60degrees, and even more preferably less than 45 degrees. In a preferredembodiment, the angle is between 15 and 45 degrees.

These higher strength absorbable self-retaining sutures can be usedeither without needing to oversize the suture for a given procedure, orby oversizing the self-retaining suture by no more than 0.1 mm indiameter. It is no longer always necessary to use an absorbableself-retaining suture that is one USP size larger than a conventionalabsorbable suture in order to meet the USP standard for initial tensilestrength of a conventional absorbable suture. A surgeon may now use thesame size of these high tensile strength self-retaining absorbablesutures as is conventionally used with non-barbed (smooth surface)absorbable sutures, or use a self-retaining absorbable suture that hasonly been oversized by less than 0.1 mm. The high tensile strengthself-retaining absorbable sutures allow the surgeon to reduce the amountof foreign material that needs to be implanted in the patient's body,decreases the size of suture tunnels in a patient's tissues, and alsoprovides more pliable sutures that can be easier to handle.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a diagram of a high tensile strength self-retaining absorbablesuture (10) showing the cut depth (18), the cut spacing (spacing betweenthe cuts) (20), the cut angle (the angle measured relative to thelongitudinal axis of the monofilament fiber) (12), and the cut length(16).

FIG. 2 is a diagram of a high tensile strength self-retaining absorbablesuture showing the difference in indentation hardness values between thedifference in indentation hardness values between the surface (sheath)of a high strength P4HB monofilament fiber (0.1535 GPaand theindentation hardness of the core of the high strength P4HBself-retaining suture (0.0289 GPa)), and the indentation hardness of theretainers (0.0961 GPa)).

FIGS. 2A-2D show self-retraining sutures (10) with retainers (30), one(FIGS. 2A-C) or more (FIG. 2D) needles (32) and looped structure (34)(FIGS. 2B-C).

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

“Absorbable” as generally used herein means the material is broken downin the body and eventually eliminated from the body within five years.

“Bioactive agent” is used herein to refer to therapeutic, prophylactic,and/or diagnostic agents. It includes without limitation physiologicallyor pharmacologically active substances that act locally or systemicallyin the body. A biologically active agent is a substance used for, forexample, the treatment, prevention, diagnosis, cure, or mitigation ofone or more symptoms of a disease or disorder, a substance that affectsthe structure or function of the body, or pro-drugs, which becomebiologically active or more active after they have been placed in apredetermined physiological environment. Bioactive agents includebiologically, physiologically, or pharmacologically active substancesthat act locally or systemically in the human or animal body. Examplescan include, but are not limited to, small-molecule drugs, peptides,proteins, sugars, polysaccharides, nucleotides and, oligonucleotides,and combinations thereof.

“Bicomponent” as generally used herein means a monofilament structuremade of two or more materials.

“Biocompatible” as generally used herein means the biological responseto the material or device being appropriate for the device's intendedapplication in vivo. Any metabolites of these materials should also bebiocompatible.

“Blend” as generally used herein means a physical combination ofdifferent polymers, as opposed to a copolymer comprised of two or moredifferent monomers.

“Copolymers of poly-4-hydroxybutyrate” as generally used herein meansany polymer of 4-hydroxybutyrate with one or more different hydroxy acidunits.

“Diameter” as generally used herein is determined according to the USPharmacopeia (USP) standard for diameter of surgical sutures (USP 861).

“Elongation to break” (“ETB”) as used herein means the increase inlength of a material that occurs when tension is applied to break thematerial. It is expressed as a percentage of the material's originallength.

“Endotoxin units” as used herein are determined using the limulusamebocyte lysate (LAL) assay as further described by Gorbet et al.Biomaterials, 26:6811-6817 (2005).

“Indentation hardness” of fiber samples as used herein is determined bya nanoindentation technique at Polymer Solutions, Inc. (Blacksburg,Va.). Samples are embedded in epoxy and polished to give a flat surfaceon which to perform testing in accordance with PSI Method ID 6137Revision 4. A diamond indenter is used to penetrate the sample with aforce of 700 μN for 50 seconds, held for 10 seconds, and then retractedwith 11 to 12 indentations made per sample. Hardness is calculated fromthe point at which the load reached a maximum using the equation H=Force(P)/Area (A), where H is hardness, P is the force and A is the area ofthe indent.

“Knot-pull tensile strength” as used herein is determined using auniversal mechanical tester according to the procedures described in theUS Pharmacopeia (USP) standard for testing tensile properties ofsurgical sutures (USP 881).

“Molecular weight” as used herein, unless otherwise specified, refers tothe weight average molecular weight (Mw), not the number averagemolecular weight (Mn), and is measured by GPC relative to polystyrene.

“Poly-4-hydroxybutyrate” as generally used herein means a homopolymer of4-hydroxybutyrate units. It may be referred to herein as P4HB orTephaFLEX® biomaterial (manufactured by Tepha, Inc., Lexington, Mass.).

“Resorbable” as generally used herein means the material is broken downin the body and eventually eliminated from the body. The terms“resorbable”, “degradable”, “erodible”, and “absorbable” are usedsomewhat interchangeably in the literature in the field, with or withoutthe prefix “bio”. Herein, these terms will be used interchangeably todescribe material broken down and gradually absorbed or eliminated bythe body, whether degradation is due mainly to hydrolysis or mediated bymetabolic processes.

“Retainer” as generally used herein means a suture element that canproject from the suture body, is adapted to penetrate tissue, and resistmovement of the suture in any direction other than the direction inwhich the suture was deployed. Examples of retainers, include, but arenot limited to, hooks, projections, barbs, darts, extensions, bulges,anchors, protuberances, spurs, bumps, points, cogs, tissue engagers,surface roughness, surface irregularities, surface defects, edges, andfacets.

“Self-retaining suture” as generally used herein means a suture thatcontains one or more elements, or tissue retainers, to allow the sutureto stay in position, and may not require a knot to maintain itsposition. In general, the tissue retainers project from the surface ofthe suture, and are designed to anchor in surrounding tissues. Suturescontaining barbs projecting from the suture surface are examples ofself-retaining sutures. Self-retaining sutures may be unidirectional,such that all the tissue retainers on the suture are oriented in thesame direction, bidirectional such that some tissue retainers areoriented in one direction and others are oriented in another direction(which is generally in the opposite direction) or multidirectional.

“Sheath-core” as described herein refers to the cross-sectionalstructure of a fiber, wherein the properties of the sheath are differentto the properties of the core, and the sheath and core cannot bephysically separated. The term should not be confused with sheath-corestructures wherein the sheath and core are two separate structures, forexample, a multifilament sheath of fibers enclosing or covering amonofilament fiber core.

“Straight pull tensile strength” means the linear breaking strength ofthe specimen. The value may be determined using a tensile testingmachine by holding the specimen between fixed and movable crossheads,and measuring the maximum tensile load per unit area of original crosssection area of the specimen.

“USP Size” as used herein means the suture size prior to barbing orforming the self-retaining suture as defined by the United StatesPharmacopeia. The USP Sizes can be 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0,2-0, 3-0, 4-0, 5-0, 6-0, 7-0, 8-0, 9-0, 10-0, 11-0 and 12-0.

II. Compositions

The compositions described herein are based on methods developed toproduce absorbable self-retaining sutures containing P4HB and copolymersthereof with high straight pull tensile strength. The self-retainingsutures are made preferably from poly-4-hydroxybutyrate (P4HB) or acopolymer thereof. In some embodiments, the PHA polymers may be blendedor mixed with other materials prior to preparing the self-retainingsutures. In addition to blending the P4HB polymers and copolymers withother polymers, additives may also be added to the polymers andcopolymers prior to preparing fibers to manufacture self-retainingsutures.

A. Monofilament Fibers and Self-Retaining Sutures

Monofilament fibers of P4HB and copolymers thereof as well asself-retaining sutures of P4HB and copolymers thereof, are provided.

i) Monofilament Fibers

Oriented P4HB fibers with very hard surfaces that are ideally suited tomaking self-retaining sutures are provided. These monofilament fibersalso have a high tensile strength and sheath-core structures.

Fibers of P4HB and copolymers thereof produced as described herein havea USP suture sizes ranging from size 4 to size 6-0 and Young's Modulusvalues that are preferably greater than 860 MPa, more preferably greaterthan 900 MPa, and even more preferably greater than 1 GPa. These valuesexceed those previously reported for monofilament fibers of P4HB andcopolymers thereof by Martin, D. et al. Medical Applications ofPoly-4-hydroxybutyrate: A Strong Flexible Absorbable Biomaterial,Biochem. Eng. J. 16:97-105 (2003), Williams, S. F. et al.Poly-4-hydroxybutyrate (P4HB): a new generation of resorbable medicaldevices for tissue repair and regeneration, Biomed. Tech. 58(5):439-452(2013), and U.S. Pat. No. 7,641,825 to Rizk. Tables 3 and 4, forexample, show the differences in Young's modulus values ofrepresentative high strength and medium strength P4HB monofilamentfibers. Notably, the Young's modulus value for the high strength size3-0 P4HB monofilament fiber is 1.8 GPa compared to just 0.79 GPa for thesize 3-0 medium strength P4HB monofilament fiber. The higher stiffness,evident from both the higher Young's modulus and indentation hardnessvalues, resulting from the pronounced sheath-core structure of the highstrength fiber is important not only for ease of placing the retainersin the fiber, but also in producing retainers that will anchor intissues and will not flex when a displacement force is applied.

The diameters of the monofilament fibers of P4HB and copolymers thereofmay range from 0.05 mm to 1 mm, but are more preferably 0.07 mm to 0.799mm, equivalent to USP suture size 6-0 to USP suture size 4 and oversizedby up to 0.1 mm. In an embodiment, the diameters may be oversizedrelative to the USP standards by up to 0.1 mm. In a more preferredembodiment, the diameters of suture sizes 6-0 to 4-0 may be oversized byup to 0.05 mm, and the diameters of suture sizes 3-0 to 4 may beoversized by up to 0.1 mm.

(ii) Self Retaining Sutures

Self-retaining sutures with diameters ranging from approximately 0.07 mmto 0.8 mm with minimum tensile strength as listed in Table 1 (exceptmeasured by straight pull), and oversized by no more than 0.1 mm indiameter. The disclosed self-retaining sutures permit a surgeon to usesmaller diameter self-retaining absorbable sutures than was previouslypossible.

The self-retaining sutures have certain properties, including: (i) endsthat can penetrate tissue, (ii) the ability to lie flat when the sutureis pulled in the deployment direction in order to generally avoidengaging with tissue, (iii) the ability to protrude from the suturesurface and engage tissue when pulled in a direction opposite to thedeployment direction so that tissue is engaged between the retainer andsuture body so the suture is anchored in place, and (iv) sufficientstiffness or hardness to anchor in tissue, and hold the suture in placewithout the retainer flexing when a force is applied in a directionopposite to the deployment direction. The retainers may take manyshapes, as. The retainers are preferably pointed or tapered at theirfree ends. The retainers may have a multi-tip configuration, inparticular a twin-tip configuration such as a W-shaped formation.Retainers with a twin-tip configuration may be made using cuts into themonofilament fiber preferably with a small angular offset and in smallintervals from each other.

The tissue retainers can be placed in a variety of differentconfigurations along the suture fiber that when implanted project fromthe suture surface into tissue and resist movement in a directionopposite to the direction the tissue retainer faces. The tissueretainers may be unidirectional, such that the tissue retainers face inthe same direction, or the tissue retainers may be oriented in abidirectional manner along the suture surface. Orientation in abidirectional manner means that a first group of at least one tissueretainer on a portion of the high strength suture is oriented in onedirection while a second group of at least one tissue retainer isoriented in another direction, more preferably in an opposite direction.

The retainers may be positioned in an ordered or random manner,including spiral, staggered and overlapping configurations. In general,helical arrays of retainers are preferable because they hold the suturein place in tissue better than retainers placed along an axis. Inaddition, the distance between the retainers (i.e. retainer density),their angles, depths, and lengths (i.e. retainer geometries) may also bevaried.

The retainers can be of various shapes, including, but not limited to,hooks, projections, barbs, darts, extensions, bulges, anchors,protuberances, spurs, bumps, points, cogs, tissue engagers, surfaceroughness, surface irregularities, surface defects, edges, facets,escutcheon-shaped, shield-shaped, scale-shaped, wedge-shaped,thorn-shaped, W-shaped, arrows, spikes, tin-shaped, V-shaped, andcombinations thereof. The retainers are preferably pointed or tapered attheir free ends. The retainers may have a multi-tip configuration, inparticular a twin-tip configuration such as a W-shaped formation. In anembodiment, the distance between the retainers may be between 0 and 25mm, but more preferably between 0 to 5 mm. Smaller distances betweenretainers are generally preferred in order to uniformly distributetension along the suture line, and to provide more consistent woundapproximation. In a preferred embodiment, the distance between retainersis preferably 0.5 to 2× the diameter of the suture.

If desired, the retainers may also be: (i) overlapped such that aretainer is cut into the fiber within the length of a prior retainer,(ii) positioned at the same distance along the fiber as anotherretainer, but in a different position on the circumference of the fiber,or (iii) positioned such that as one retainer ends another retainerstarts either along the same axis or located somewhere else around thecircumference of the fiber. In another embodiment, groups of retainersmay be cut into the fibers, and larger spaces without retainers leftbetween single retainers or groups of retainers.

In an embodiment, the length of the retainer may range from 0.25 to 2×the diameter of the suture, more preferably from 0.25 to 1.5× thediameter of the suture, and even more preferably equal 0.25 to 1.25× thediameter of the suture. Thus, the length of the retainer can be between0.01-10 mm.

The straight pull tensile strengths of these absorbable self-retainingsutures exceed the average minimum knot-pull tensile strength standardsset by the United States Pharmacopoeia (USP) with either no oversizingof the suture of at most oversizing of 0.1 mm or less.

The United States Pharmacopoeia (USP) defines sizes of absorbablesutures, and the average minimum knot-pull tensile strengths for a givenabsorbable suture size. The sizes, minimum and maximum averagediameters, and average minimum knot-pull tensile strengths (in kgf)defined by the USP standard are shown in Table 1. Thus, for example, asize 5-0 suture must have a minimum average diameter of 0.1 mm, amaximum average diameter of 0.149 mm, and a minimum average knot-pulltensile strength of 0.68 kgf. It will be apparent by inspection of Table1 that the knot-pull tensile strength of an absorbable suture increasesas the diameter of the suture increases. The values shown in Table 1 aredetermined according to procedures defined in the US Pharmacopeia.

TABLE 1 Knot-Pull Tensile Strengths Defined by the USP Standards forDifferent Absorbable Suture Sizes USP Knot-Pull Tensile Suture AverageMin. Average Max. Strength (Average Min. Size Diameter (mm) Diameter(mm) kgf) 10-0  0.020 0.029 0.025* 9-0 0.030 0.039 0.050* 8-0 0.0400.049 0.07 7-0 0.050 0.069 0.14 6-0 0.070 0.099 0.25 5-0 0.10 0.149 0.684-0 0.15 0.199 0.95 3-0 0.20 0.249 1.77 2-0 0.30 0.339 2.68 0 0.35 0.3993.90 1 0.40 0.499 5.08 2 0.50 0.599 6.35 3 and 4 0.60 0.699 7.29 *Thetensile strength of these sizes is measured by straight pull

Notably, the US Pharmacopeia generally requires a manufacturer to reportthe knot-pull tensile strength of a suture rather than the straight-pulltensile strength because the former recognizes the reduction in strengththat occurs when a suture is knotted. Self-retaining sutures are,however, an exception to this rule because self-retaining sutures aregenerally designed for use without a knot [see: Greenberg, J. A. Rev.Obstet. Gynecol. 3(3):82-91 (2010)]. Therefore, manufacturers report thetensile strengths of self-retaining sutures measured by straight pull,and compare these test values to the knot-pull tensile strengthstandards of the US Pharmacopeia. This approach makes sense since for aself-retaining suture its tissue holding capacity is most accuratelyreflected by its straight-pull tensile strength whereas the tissueholding capacity of a suture that needs to be knotted is most accuratelyreflected by its knot-pull tensile strength.

The standards for absorbable sutures set by the US Pharmacopeia areimportant to surgeons because they provide a standard system across alldifferent types of absorbable suture sizes, regardless of material type,that allows the surgeon to select a specific suture size knowing that itwill have sufficient initial mechanical properties (i.e. tensilestrength) appropriate for an intended repair. For example, a surgeonselecting a size 3-0 absorbable suture expects the suture to have aminimum tensile strength of at least 1.77 Kgf, and that this strength isachieved within the set diameter range for a size 3-0 suture, namelyfrom 0.20 to 0.249 mm. If however a suture does not meet the USPstandard for tensile strength, it means that a surgeon may have to use alarger size of suture so that the suture has sufficient strength for theintended repair. In general, however, surgeons do not want to use largersizes of suture than is absolutely necessary, and therefore it isimportant that sutures meet the USP standards or do not stray far fromthe standards. For example, a plastic surgeon undertaking a face-liftprocedure will generally prefer to use sutures that meet or approximatethe USP standard since the surgeon will not want to place largersutures, and therefore more foreign material, in the patient's face inorder to provide adequate tensile strength. The surgeons also generallyprefer to keep the suture tunnel in the tissue as small as possible, andthe pliability of the suture as high as possible so it is easy toimplant. Both of these latter requirements are lost if the surgeon hasto use a substantially larger diameter suture because the suture doesnot meet or approximate the USP standards for tensile strength.

A major advantage of the absorbable self-retaining sutures is that thesutures meet the requirements of the USP standards for knot pullstrength (as measured by straight pull) or closely approximate therequirements of the USP standards. Notably, the absorbableself-retaining sutures do not need to be oversized by more than 0.1 mmin diameter to meet the USP standards, if at all. This means that asurgeon does not need to use an absorbable self-retaining suture that isboth one size larger and oversized in order to have the tensile strengthof a conventional suture. This reduces the amount of foreign materialthat needs to be implanted in a patient, and also reduces the size ofsuture tunnels made in the patient's tissues. Since the self-retainingsutures are absorbable, it also means that the time to completedegradation can, if desired, be faster in certain cases. Removing therequirement to use a self-retaining suture that is one size larger alsomeans that the surgeon can work with a more pliable suture makingimplantation easier.

The high tensile strength absorbable self-retaining sutures of P4HB andcopolymers thereof provided herein are biocompatible and can be used insoft and hard tissue repair, replacement, remodeling, and regeneration.Examples of applications for these high strength absorbableself-retaining sutures include wound closure, breast reconstruction andbreast lift, including mastopexy procedures, lift procedures performedon the face such as face-lifts, neck lifts, and brow lifts, and ligamentand tendon repair.

Self-retaining sutures can be made where all the tissue retainers facein the same direction, or different directions, for example, where thetissue retainers are oriented bi-directionally along the suture surface.The retainers may be positioned in an ordered or random manner,including spiral, staggered and overlapping configurations. In addition,the distance between the retainers, their angles, depths, and lengthsmay also be varied.

The straight pull tensile strengths of the monofilament fibers of P4HBand copolymers thereof produced by the processes described herein allowthese fibers, with no more than a 0.1 mm variance in fiber diameter, tobe converted to self-retaining sutures with the following minimumstraight pull tensile strengths:

(i) 0.25 Kgf for a USP size 6-0 self-retaining suture; (ii) 0.68 Kgf fora USP size 5-0 self-retaining suture; (iii) 0.95 Kgf for a USP size 4-0self-retaining suture; (iv) 1.77 Kgf for a USP size 3-0 self-retainingsuture; (v) 2.68 Kgf for a USP size 2-0 self-retaining suture; (vi) 3.9Kgf for a USP size 0 self-retaining suture; (vii) 5.08 Kgf for a USPsize 1 self-retaining suture; (viii) 6.35 Kgf for a USP size 2self-retaining suture; and (ix) 7.29 Kgf for a USP size 3 or 4self-retaining suture. In an embodiment, the monofilament fibers of P4HBand copolymers thereof used to make the self-retaining sutures lose only30-40% of their straight pull tensile strength when retainers areinserted in the fibers. In another embodiment, the monofilament fibersof P4HB and copolymers thereof used to make the self-retaining sutureshave at least 2 times the straight pull tensile strength of theself-retaining sutures, and even more preferably at least 2.5 times thestraight pull tensile strength of the self-retaining sutures.

Table 2 illustrates the difference in straight pull tensile strength ofthe self-retaining sutures made from high tensile strength monofilamentfibers of P4HB compared to Quill's PDO absorbable self-retaining sutures(data taken from Angiotech product package insert P/N 03-5278R3) versusthe USP standard. Both self-retaining sutures may be oversized by up to0.1 mm, however, the Quill self-retaining sutures also need to be onesize larger to meet the USP standard for tensile strength. In contrast,the high tensile strength P4HB self-retaining sutures do not need to beone size larger to meet the USP standard for tensile strength.

TABLE 2 Comparison of diameters of oversized Quill PDO and P4HB self-retaining sutures to the USP standard Quill PDO Self- USP TensileStrength retaining suture, P4HB Self-retaining Suture (Average Min.oversized suture, oversized by Size Kgf) by up to 0.1 mm up to 0.1 mm5-0 0.68 4-0 5-0 4-0 0.95 3-0 4-0 3-0 1.77 2-0 3-0 2-0 2.68 0 2-0 0 3.901 0 1 5.08 2 1

B. Polymers The high strength absorbable self-retaining sutures comprisepoly-4-hydroxybutyrate (P4HB) or a copolymer thereof. Copolymers include4-hydroxybutyrate copolymerized with another hydroxyacid, such as3-hydroxybutyrate, and 4-hydroxybutyrate copolymerized with glycolicacid or lactic acid monomer.

Poly-4-hydroxybutyrate is not a natural product, and has never beenisolated from a naturally occurring source. Poly-4-hydroxybutyrate(P4HB) can be produced, however, using transgenic fermentation methods,see, for example, U.S. Pat. No. 6,548,569 to Williams et al., and isproduced commercially, for example, by Tepha, Inc. (Lexington, Mass.).Copolymers of poly-4-hydroxybutyrate can also be produced by transgenicfermentation methods, see also U.S. Pat. No. 6,548,569 to Williams etal.

Poly-4-hydroxybutyrate (P4HB, TephaFLEX® biomaterial) is a strong,pliable thermoplastic polyester that, despite its biosynthetic route,has a relatively simple structure. Upon implantation, P4HB hydrolyzes toits monomer, and the monomer is metabolized via the Krebs cycle tocarbon dioxide and water.

Although man-made, P4HB belongs to a larger class of materials calledpolyhydroxyalkanoates (PHAs). PHA polymers include naturally occurringpolymers produced by wildtype (naturally occurring) microorganisms, andPHA polymers that, like P4HB, are not naturally occurring [see, forexample, Steinbüchel A., et al. Diversity of BacterialPolyhydroxyalkanoic Acids, FEMS Microbial. Lett. 128:219-228 (1995) andAgnew D. E. and Pfleger, B. F. Synthetic biology strategies forsynthesizing polyhydroxyalkanoates from unrelated carbon sources,Chemical Engineering Science 103:58-67 (2013)].

Chemical synthesis of P4HB has been attempted, but it has beenimpossible to produce the polymer with a sufficiently high molecularweight that is necessary for most applications, including meltprocessing [see Hori, Y., et al., Polymer 36:4703-4705 (1995); Houk, K.N., et al., J. Org. Chem., 2008, 73 (7), 2674-2678; and Moore, T., etal., Biomaterials 26:3771-3782 (2005)]. In fact, it has been calculatedto be thermodynamically impossible to chemically synthesize a highmolecular weight homopolymer under normal conditions [Moore, T., et al.,Biomaterials 26:3771-3782 (2005)]. Chemical synthesis of P4HB insteadyields short chain oily oligomers that lack the desirable thermoplasticproperties of the high molecular weight P4HB polymers produced bybiosynthetic methods.

It should be noted that the literature commonly refers to anotherpolyhydroxyalkanoate, poly-3-hydroxybutyrate (P3HB), simply aspolyhydroxybutyrate (PHB) (see Section 2 of Moore, T., et al.,Biomaterials 26:3771-3782 (2005)). Unlike P4HB, PHB is naturallyoccurring, and has entirely different properties to P4HB. PHB isstructurally and functionally different to P4HB. For example, PHB has amelting point of 180° C. versus a melting point of about 61° C. forP4HB. The polymers also have substantially different glass transitiontemperatures and mechanical properties. For example, PHB is a relativelyhard brittle polymer with an extension to break of just a few percent,whereas P4HB is a strong extensible polymer with an extension to breakof about 1000%. As such, PHB has properties resembling polystyrenewhereas P4HB has properties more similar to low density polypropylene.Not surprisingly, substantially different conditions are required toprocess these two polymers, and the resulting products havesubstantially different properties.

U.S. Pat. Nos. 6,245,537, 6,623,748, 7,244,442, and 8,231,889 describemethods of making PHA polymers with little to no endotoxin, which aresuitable for medical applications. U.S. Pat. Nos. 6,548,569, 6,838,493,6,867,247, 7,268,205, 7,179,883, 7,268,205, 7,553,923, 7,618,448 and7,641,825 and WO 2012/064526 describe use of PHAs to make medicaldevices. Copolymers of P4HB include 4-hydroxybutyrate copolymerized with3-hydroxybutyrate or glycolic acid (U.S. Pat. No. 8,039,237 to Martinand Skraly, U.S. Pat. No. 6,316,262 to Huisman et al., and U.S. Pat. No.6,323,010 to Skraly et al.). Methods to control molecular weight of PHApolymers have been disclosed by U.S. Pat. No. 5,811,272 to Snell et al.

PHAs with controlled degradation and degradation in vivo of less thanone year are disclosed by U.S. Pat. Nos. 6,548,569, 6,610,764,6,828,357, 6,867,248, and 6,878,758 to Williams et al. and WO 99/32536to Martin et al. Applications of P4HB have been reviewed in Williams, S.F., et al., Polyesters, III, 4:91-127 (2002), Martin, D. et al.,Biochem. Eng. J. 16:97-105 (2003), and by Williams, S. F. et al.,Biomed. Tech. 58(5):439-452 (2013). Medical devices and applications ofP4HB have also been disclosed by WO 00/56376 to Williams et al. Severalpatents including U.S. Pat. Nos. 6,555,123, 6,585,994, and 7,025,980describe the use of PHAs in tissue repair and engineering.

U.S. Pat. No. 8,034,270 to Martin et al. discloses monofilament andmultifilament knitted meshes of P4HB produced by knitting monofilamentand multifilament fibers of P4HB. WO 2011/119742 to Martin et al.discloses P4HB monofilament and multifilament fiber, coatings and spinfinishes for these fibers, and medical devices made from P4HBmonofilament and multifilament fibers. U.S. Pat. No. 8,016,883 toColeman et al. discloses methods and devices for rotator cuff repair,including medical devices containing knitted meshes of P4HB andnonwovens made from P4HB multifilament fibers.

U.S. Pat. No. 8,287,909 to Martin et al. discloses medical devicescontaining melt-blown nonwovens of poly-4-hydroxybutyrate and copolymersthereof with average fiber diameters of 1 μm to 50 μm. WO 2011/159784 toCahil et al. discloses medical devices containing dry spun nonwovens ofP4HB and copolymers thereof, and continuous processing methods for theirpreparation.

Odermatt et al., Int. J. Polymer Science, Article 216137, 12 pages(2012) and U.S. Pat. Nos. 7,641,825 and 8,084,125 to Rizk disclosenon-curling sutures of P4HB. Odermatt et al. and Rizk do not disclosehigh strength absorbable self-retaining P4HB sutures. Instead theydisclose P4HB suture fiber that has not been highly oriented, and hasbeen relaxed to reduce the curling of the suture fiber. Relaxing thesuture fiber decreases the tensile strength of the fiber. For example,the tensile strength of the relaxed size 3/0 suture fiber reported byRizk is 4.148 Kgf, compared to 6.9 Kgf.

US Patent Application No. 2010/0057123 to D'Agostino and Rizk, and USPatent Application No. 2009/0112259 to D'Agostino disclose recombinantexpressed bioabsorbable polyhydroxyalkanoate monofilament andmulti-filament self-retaining sutures. There is no disclosure of thestraight pull tensile strength of the self-retaining sutures, and nodisclosure of how to produce self-retaining PHA sutures with hightensile strength. The applications do disclose the extensions to breakranging from 8% to 42% for the self-retaining sutures, however, itshould be noted that the applications do not disclose the extensions tobreak of the PHA monofilament fibers used to make the self-retainingsutures. In fact, the applications do not disclose any details regardingthe properties of PHA monofilament fibers that are necessary to makeself-retaining sutures. There is absolutely no disclosure of how to makePHA self-retaining sutures that have straight pull tensile strengthsthat approximate, equal or exceed the average minimum knot-pull tensilestrength standards set by the United States Pharmacopeia (USP). There isno disclosure recognizing the potential to produce, or need to produce,self-retaining sutures that approximate or meet the requirements of theUSP standards for both diameter and tensile strength, nor any disclosureof the problems that can be overcome by producing such high strengthself-retaining sutures that approximate or meet the USP standards forabsorbable sutures. There is also no disclosure of the problems thatneed to be overcome in order to manufacture a PHA self-retaining suturewith a tensile strength that approximates, equals or exceeds the averageknot-pull tensile strength standard set by the USP.

US Patent Application No. 2012/0053689 to Martin et al. discloses barbedsutures made from polyhydroxyalkanoate polymers, including devicescomprising a monofilament core with an outer multifilament sheath (suchthat the barbed monofilament core anchors the outer multifilamentsheath). Martin et al. do not disclose self-retaining sutures with highstraight pull tensile strength, or self-retaining sutures with suchstrength that approximates, equals or exceeds the average minimumknot-pull tensile strength standards set by the USP. In fact, there isno disclosure recognizing the potential to produce, how to produce, orneed to produce, self-retaining sutures that approximate or meet therequirements of the USP standards for both diameter and tensilestrength.

In a preferred embodiment, the P4HB homopolymer and copolymers thereofused to prepare the high tensile strength self-retaining sutures have aweight average molecular weight, Mw, within the range of 50 kDa to 1,200kDa (by GPC relative to polystyrene) and more preferably from 100 kDa to600 kDa.

If desired, the PHA polymers may be blended or mixed with othermaterials prior to preparing the self-retaining sutures. In a preferredembodiment, P4HB and its copolymers may be blended with other absorbablepolymers. Examples of other absorbable polymers include, but are notlimited to, polymers containing glycolic acid, lactic acid,1,4-dioxanone, trimethylene carbonate, 3-hydroxybutyric acid, andε-caprolactone, and include polyglycolic acid, polyglycolide, polylacticacid, polylactide, polydioxanone, polycaprolactone, copolymers ofglycolic and lactic acids such as VICRYL® polymer, and the MAXON® andMONOCRYL® polymers. If desired, the P4HB homopolymer and copolymersthereof may also be blended with natural absorbable polymers, such ascollagen, silk, proteins, polysaccharides, glycosaminoglycans,hyaluronic acid, heparin, and chitosan, as well as other componentsprior to preparing PHA fibers suitable for making the self-retainingsutures. The ratio of the PHA polymer in the blend to the non-PHApolymer component(s) may be varied in order to select the desiredproperties of the self-retaining suture. However, the ratio of thenon-PHA to the PHA polymer should not be so high that it causes theresulting self-retaining suture to have a straight pull tensile strengthless than, or approximate to, the average minimum knot-pull tensilestrength standard set by the United States Pharmacopoeia (USP). Thisalso applies to copolymers of P4HB. The ratio of co-monomers in a P4HBcopolymer should not be so high that it causes the self-retaining sutureto have a straight pull tensile strength less than, or approximate to,the average minimum knot-pull tensile strength standard set by theUnited States Pharmacopoeia (USP). In an embodiment, a self-retainingsuture made from a P4HB copolymer or blend of P4HB with another materialmeet the USP standard except the suture may be oversized by up to 0.1 mmin diameter.

C. Additives

In addition to blending the P4HB polymers and copolymers with otherpolymers, additives may also be added to the polymers and copolymersprior to preparing fibers to manufacture self-retaining sutures.Preferably, these additives are incorporated during the compoundingprocess to produce pellets that can be subsequently processed intofibers suitable for making high strength self-retaining sutures. Inanother embodiment, the additives may be incorporated using asolution-based process. In a preferred embodiment, the additives arebiocompatible, and even more preferably the additives are bothbiocompatible and absorbable.

In one embodiment, the additives may be nucleating agents and/orplasticizers. These additives may be added in sufficient quantity toproduce the desired result. In general, these additives may be added inamounts of up to 20% by weight. Nucleating agents may be incorporated toincrease the rate of crystallization of the P4HB homopolymer, copolymeror blend. Such agents may be used to improve the mechanical propertiesof fibers, and to reduce cycle times. Preferred nucleating agentsinclude, but are not limited to, salts of organic acids such as calciumcitrate, polymers or oligomers of PHA polymers and copolymers, highmelting polymers such as PGA, talc, micronized mica, calcium carbonate,ammonium chloride, and aromatic amino acids such as tyrosine andphenylalanine.

Plasticizers that may be incorporated into the compositions include, butare not limited to, di-n-butyl maleate, methyl laureate, dibutylfumarate, di(2-ethylhexyl) (dioctyl) maleate, paraffin, dodecanol, oliveoil, soybean oil, polytetramethylene glycols, methyl oleate, n-propyloleate, tetrahydrofurfuryl oleate, epoxidized linseed oil, 2-ethyl hexylepoxytallate, glycerol triacetate, methyl linoleate, dibutyl fumarate,methyl acetyl ricinoleate, acetyl tri(n-butyl) citrate, acetyl triethylcitrate, tri(n-butyl) citrate, triethyl citrate, bis(2-hydroxyethyl)dimerate, butyl ricinoleate, glyceryl tri-(acetyl ricinoleate), methylricinoleate, n-butyl acetyl rincinoleate, propylene glycol ricinoleate,diethyl succinate, diisobutyl adipate, dimethyl azelate, di(n-hexyl)azelate, tri-butyl phosphate, and mixtures thereof. Particularlypreferred plasticizers are citrate esters.

Other additives that can be incorporated into the P4HB polymer andcopolymers thereof include, but are not limited to, compatibilizers,porogens, dyes, and organic or inorganic powders including fillers andbioceramics. Particularly preferred bioceramics are degradable, andinclude tricalcium phosphate (α and β forms of TCP—with a nominalcomposition of Ca₃(PO₄)₂), biphasic calcium phosphate (BCP), calciumsulfate, calcium carbonate, hydroxyapatite and other calcium phosphatesalt-based bioceramics. Bio-active glasses may also be incorporatedprior to preparing fibers suitable for making high tensile strengthself-retaining sutures.

It may also be advantageous to incorporate contrast agents, radiopaquemarkers, imaging agents, or radioactive substances into the P4HB polymerand copolymers thereof prior to spinning fibers suitable for making hightensile strength self-retaining sutures. Alternatively, these can beincorporated into or onto the high tensile strength self-retainingsutures during subsequent processing steps.

The self-retaining sutures may also be coated with materials to furtherimprove their performance. For example, the self-retaining sutures maybe coated to improve their lubricity. Coatings that can be applied toincrease the lubricity of the self-retaining sutures include wax,natural and synthetic polymers such as polyvinyl alcohol, and spinfinishes including TWEEN® 20, and polymers or oligomers of ethyleneoxide and propylene oxide. These coatings are preferably applied so theself-retaining suture to a coating weight of less than 6 wt %, and morepreferably less than 3 wt %. It is preferred that the coatings readilyleave the surface of the self-retaining suture in vivo, for example, bydegradation or dissolution, for example, being formed of a water-solublematerial which dissolves.

D. Bioactive Agents

In an embodiment, bioactive agents may be incorporated into the P4HBpolymer or copolymer thereof. Bioactive agents may be incorporatedeither prior to spinning fibers suitable for making high tensilestrength self-retaining sutures, for example, during blending orpelletization, or alternatively, these agents may be incorporated intoor onto the high tensile strength self-retaining sutures duringsubsequent processing steps. In one embodiment, the bioactive agents,and the P4HB polymer or copolymer thereof, may be dissolved in a solventor solvent system in order to disperse the bioactive agent in the P4HBpolymer or copolymer thereof, and the solvent may then be removed byevaporation. Preferred solvents include methylene chloride, chloroform,tetrahydrofura, acetone, dimethylformamide, and 1,4-dioxane.

Examples of bioactive agents that can be incorporated into the P4HBpolymer, copolymer, or blends thereof, include, but are not limited to,small-molecule drugs, anti-inflammatory agents, immunomodulatory agents,molecules that promote cell migration, molecules that promote or retardcell division, molecules that promote or retard cell proliferation anddifferentiation, molecules that stimulate phenotypic modification ofcells, molecules that promote or retard angiogenesis, molecules thatpromote or retard vascularization, molecules that promote or retardextracellular matrix disposition, and signaling ligands. These may besynthetic or nature materials such as platelet rich plasma, peptides,proteins, glycoproteins, sugars, polysaccharides, lipids, lipoproteins,nucleotides and oligonucleotides such as antisense molecules, aptamers,and siRNA, inorganics such as hydroxyapatite and silver particles, orsmall molecules. Examples include anesthetics, hormones, antibodies,growth factors, fibronectin, laminin, vitronectin, integrins,antibiotics, steroids, vitamins, non-steroidal anti-inflammatory drugs,chitosan and derivatives thereof, alginate and derivatives thereof,collagen, hyaluronic acid and derivatives thereof, allograft material,xenograft material, ceramics, and combinations thereof.

III. Methods of Manufacturing High Strength Self-Retaining Sutures ofP4HB and Copolymers Thereof

A. Methods of Manufacturing Fibers

Methods are provided for manufacturing monofilament fibers of P4HB andcopolymers thereof with high tensile strength, sheath-core structures,and high surface hardness, as well as self-retaining sutures of P4HB andcopolymers thereof.

In a preferred embodiment, these monofilaments are prepared by fiberspinning.

In a particularly preferred embodiment, the monofilament fibers used tomake the high tensile strength self-retaining sutures are made by meltextrusion. In one embodiment, P4HB monofilament fibers may be preparedusing an American Kuhne melt extruder with a 1.5 inch extruder barrel,fitted with an extrusion screw with a 30:1 L/D ratio, and containing 5heating zones, by (i) drying bulk P4HB resin in pellet form until it hasa water content of less than 300 ppm using a rotary vane vacuum pumpsystem, (ii) transferring the dried pellets to the feed hopper of theextruder fitted with a dry nitrogen purge to keep the pellets dry, (iii)gravity feeding the P4HB pellets into a chilled feeder section,introducing the pellets into the extruder barrel, feeding the heated andsoftened resin into a heated metering pump (melt pump), and from themetering pump feeding the resin into a heated block and an eight-holespinneret assembly (using a processing profile of 40° C. to 260° C. fortemperatures, and 400 psi to 2,000 psi for pressures) (iv) waterquenching the molten P4HB monofilaments, and (v) conveying the quenchedfilaments into a multi-stage orientation line, and stretching of atleast 6×, before winding the high strength P4HB monofilament fiber onspools.

As well as providing high tensile strength fibers of P4HB and copolymersthereof, the procedure described above also produces P4HB fibers withvery hard surfaces that are ideally suited to making self-retainingsutures. Moreover, it has been discovered that oriented fibers of P4HBand copolymers thereof can be produced with well-defined sheath-corestructures in which the sheath has a highly oriented crystallinestructure while the core, although still semi-crystalline, has lessorientation than the sheath. The differences in orientation andcrystallinity between the sheath and the core mean that the fiber has ahard surface and a softer inner core.

Adjustment of the monofilament fiber orientation process allows thehardness of the fiber surface to be regulated, and permits theproduction of high strength self-retaining sutures of P4HB andcopolymers thereof. Thus, monofilament fibers with increased surfacehardness values may be obtained by increasing the draw ratio duringorientation of the fibers of P4HB and copolymers thereof. The draw ratiois preferably at least 6×, more preferably at least 6.5×, and even morepreferably at least 7×. In a particularly preferred embodiment the drawratio is 7.2× or more. Importantly, unlike prior disclosures such asU.S. Pat. Nos. 7,641,825 and 8,084,125 to Rizk, the monofilament fiberis not significantly relaxed in a separate step after orientation. Forexample, the oriented monofilament fiber is not stretched 7×, and thenallowed to relax to a draw ratio of 6.5× as shown in ComparativeExample 1. Relaxation results in a significant decrease in tensilestrength of the fiber, and a significant decrease in surface hardness.Table 3 shows the difference in indentation hardness values between thesurface (sheath) and core of high strength P4HB monofilament fibers, andthe difference in indentation hardness values between the surface of ahigh strength P4HB self-retaining suture, the core of a high strengthP4HB self-retaining suture, and the surface of a medium strength P4HBmonofilament fiber. Several conclusions may be drawn from Table 3.First, it is clear that for the medium strength P4HB monofilament fiber,the indentation hardness of the surface (0.0473) is significantly lessthan that of the high strength P4HB monofilament fiber (0.1535 GPa). Andsecond, the indentation hardness of the retainers of the high strengthP4HB self-retaining suture (0.0961 GPa) is much higher than theindentation hardness of the core of the high strength P4HBself-retaining suture (0.0289 GPa).

TABLE 3 Indentation hardness (GPa) comparing indentation hardness ofP4HB monofilament fiber samples Sample Indentation Hardness (GPa) Mediumstrength P4HB monofilament fiber, 0.0473 size 2, 55% ETB, SURFACE Highstrength P4HB monofilament fiber, 0.1535 size 2, 25% ETB, SURFACE Highstrength P4HB self-retaining suture, 0.0289 size 2, 25% ETB, CORE Highstrength P4HB self-retaining suture, 0.0961 size 2, 25% ETB, SURFACE(RETAINER)

The hardness of a fiber's surface is an important property in thepreparation of self-retaining sutures. For example, if the surface istoo soft, it will be difficult to cut retainers in the fiber surface.This is because the surface of a soft suture fiber will plasticallydeform when a cutting machine applies pressure. The deformation of thefiber surface may either prevent the fiber from being cut, or result ina sub-optimal cut. Not only will it be difficult to cut the surface ofthe fiber if the fiber surface is too soft, but the retainers cut in thesuture will not be hard enough to anchor in tissue, and will flex andnot be retained in the tissue when a force is applied. Consequently, thediscovery that unoriented P4HB fibers with very soft surfaces (e.g.tensile modulus of 70 MPa) can be oriented to provide fibers withsheath-core structures containing very hard surfaces is important in theproduction of high tensile strength P4HB self-retaining sutures andtheir ability to anchor securely in a patient's tissues.

B. Introduction of Retainers in High Tensile Strength AbsorbableMonofilament Fibers

In an embodiment, the absorbable self-retaining sutures are made byinserting retainers in the high tensile strength absorbable monofilamentfibers of P4HB and copolymers thereof.

Referring to the self-retaining suture (10) shown in FIG. 1, in oneembodiment, the angle (12) of the cut forming the retainer (14) measuredrelative to the longitudinal axis of the suture fiber (10) is less than90 degrees, more preferably less than 60 degrees, and even morepreferably less than 45 degrees. In a preferred embodiment, the angle(12) is between 15 and 45 degrees. The angle (12) and cut length (16)determine the depth (18) of the cut.

Retainers may be cut into the high tensile strength absorbablemonofilament fiber (20) to any depth (18) provided the cuts are not sodeep that it causes the resulting self-retaining suture to have astraight pull tensile strength less than the average minimum knot-pulltensile strength standard set by the United States Pharmacopoeia (USP).The exact depth of the cuts in the monofilament fiber will depend on thediameter of the self-retaining suture that is being produced. Typically,the depths (18) of cuts in the monofilament fibers, measuredperpendicular from the monofilament surface, will be in the range of 1.0to 300 μm, depending upon the diameter of the self-retaining suture thatis being produced. In an embodiment, the depth of retainers cut into thehigh strength absorbable monofilament fiber may be up to 40% or more ofthe diameter of the monofilament fiber.

In an embodiment, the retainer-forming step includes cutting the hightensile strength absorbable monofilament fiber with a cutting elementpositioned at a desired angle relative to the longitudinal axis of themonofilament (see angle shown in FIG. 1). The cutting element iscontrolled such that it makes the cut not only at a desired angle (12),but also for a desired length (16) and depth (18). Additional retainersmay be cut in the fiber at any desired distance from each other (20),and also, if desired, placed around the circumference of the fiber (forexample, to make a helical pattern). The angles, lengths and depths ofthe retainers cut in the fiber may also be varied.

The cuts in the fiber may be made by any suitable method, includingsimply using a cutting blade or more preferably micromachining equipmentdesigned to cut retainers of various shapes, lengths, and depths intothe fiber at different angles and also, if desired, placing theretainers around the circumference of the fiber. In another embodiment,the retainers may be cut using a laser. In a particularly preferredembodiment, micromachining is used to manufacture the self-retainingsutures from the high tensile strength monofilament fibers. Methods forplacing retainers in monofilament fibers are known in the art, and canbe used to place retainers in the monofilament fibers of P4HB andcopolymers thereof. For example, a method of making a self-retainingsuture by varying the blade geometry and/or the movement of the bladewhen cutting a fiber is described in U.S. Pat. No. 6,848,152. A stationfor forming barbs in a suture is disclosed in U.S. Patent ApplicationNo. 2010 0275750. U.S. Pat. No. 8,032,996 discloses an apparatus forforming barbs on a suture. The apparatus has a filament supply and anin-feed collet for holding one end of a filament threaded there through.Further the apparatus has an out-feed collet for holding a second end ofa filament threaded there through. The apparatus also has a holderpositioned between the in-feed and out-feed collets for holding afilament suspended between the in-feed and out-feed collets. Theapparatus also has a cutting assembly for cutting barbs in the filamenttensioned between the in-feed and out-feed collets.

C. Incorporation of Bioactive Agents in High Tensile Strength AbsorbableSelf-Retaining Sutures

Bioactive agents may be incorporated into the high tensile strengthabsorbable self-retaining sutures either prior to spinning of the highstrength monofilament fiber, prior to inserting retainers in themonofilament fiber, or after retainers have been inserted in themonofilament fiber. In the former case, the bioactive agents may beblended with poly-4-hydroxybutyrate and copolymers thereof prior tospinning. Alternatively, the bioactive agents may be applied to themonofilament fiber before or after inserting retainers. In oneembodiment, the bioactive agents may be dissolved to form a solution orsuspended in a solution, and applied to the fiber. Solutions andsuspensions may be applied to the fiber by spray coating, dip-coating,immersion, painting, electrostatic spraying, pad printing, wiping, andbrushing. In a preferred embodiment, the bioactive agents are dissolvedin non-solvents for poly-4-hydroxybutyrate and copolymers thereof sothat the bioactive agents may be applied to the fiber withoutsolubilizing the fiber or softening the fiber surface. After applicationof the bioactive agents, non-volatile solvents, such as water, may beremoved by vacuum drying. This is particularly important to protect thesuture from hydrolysis, and loss of polymer molecular weight. Solventsthat may be used to coat the fibers with bioactive agents include, butare not limited to, water, alcohols including methanol, ethanol andisopropanol, ether, hexane and other non-polar organic solvents.

D. Structures Containing Self-Retaining High Tensile Strength AbsorbableSutures

The high tensile strength self-retaining absorbable sutures may be usedin suturing applications with or without needles. Needles may be swagedonto both ends of the bidirectional self-retaining sutures, or thebidirectional self-retaining sutures may be used without needles.

Needles are generally only swaged onto one end of the unidirectionalself-retaining sutures (although they may be swaged onto both ends). Theother end of a unidirectional self-retaining suture is usuallyconfigured into a closed loop to facilitate the initial fixation of theself-retaining suture. In general, it is preferable to use lesstraumatic needles in terms of tip design and diameter in order toimprove the holding of the self-retaining suture in tissues. In anembodiment, the ratio of the needle diameter to the suture fiberdiameter is less than 3, more preferably less than 2, and even morepreferably less than 1.5.

The self-retaining sutures may also be incorporated as components ofmedical devices. For example, the self-retaining sutures may beincorporated into devices that after implantation need to be fixed inplace, and wherein the self-retaining suture can be secured in softtissue to fix the device in place. In one embodiment, the self-retainingsutures may be incorporated into surgical meshes and non-wovenconstructs. Such meshes may be used in applications including herniarepair, pelvic floor reconstruction, tendon and ligament repair, breastreconstruction, plastic surgery including mastopexy, breastaugmentation, face-lift, forehead lift, neck lift, brow lift, eyelidlift, and cosmetic repairs. In another embodiment, the self-retainingsutures may be incorporated inside another device or structuralcomponent of a device, for example, to provide reinforcement to thedevice. For example, one or more self-retaining sutures may be insertedinside a braided tube or covered with a sheath of multifilament. In apreferred embodiment, the retainers anchor the suture in the device. Theretainers may or may not protrude from the sheath of the device.

E. Sterilization of High Tensile Strength Self-Retaining Sutures

In a preferred embodiment, the high tensile strength self-retainingsutures (or structures comprising these sutures) may be sterilized usingethylene oxide gas, and even more preferably using an ethylene oxidecold cycle. In another preferred embodiment, the high tensile strengthsutures (or structures comprising these sutures) may be sterilized withelectron-beam irradiation or gamma-irradiation. In another embodiment,the high strength self-retaining sutures may be sterilized usingalcohol.

IV. Methods of Implanting High Strength Self-Retaining Sutures andApplications

The self-retaining sutures may be implanted in straight lines. However,it is generally preferable, although not always, to implant theself-retaining sutures in a configuration that is not a straight line.It is believed that the self-retaining sutures anchor better in tissuewhen the self-retaining sutures are placed in winding, twisting, ormeandering patterns so that the retainers encounter more collagen toensnare. In contrast, if the self-retaining suture is placed in astraight line, there is a risk that a loosened tunnel of tissue may formaround the suture if the suture begins to pull out. Greater holdingstrength may therefore be achieved if the self-retaining suture isplaced, for example, with a “J” stitch rather than a straight stitch.Similarly, the self-retaining suture may be placed in otherconfigurations, such as “U”, “C”, “S” or “M” patterns, to providegreater holding strength.

The high strength absorbable self-retaining sutures may be used inprocedures where temporary support is required. For example, the suturesmay be used in certain repair and remodeling procedures. Theself-retaining sutures may be used in the approximation of wounds,including deep wounds, and may be used to reduce the formation of widescars and wound hernias. This may be possible, for example, in caseswhere a self-retaining suture can more evenly spread the tension in awound when compared to the use of a conventional smooth knotted suture.

In a particularly preferred embodiment, the self-retaining sutures areused in plastic surgery procedures, and even more preferably in liftprocedures. The sutures may be used, for example, to approximate tissuesin the face, neck and breast, and to elevate these tissues. For example,the self-retaining sutures may be used to elevate a ptotic breast inmastopexy procedures, either using just sutures or in combination withother materials, such as a surgical mesh. The sutures may also beanchored to the superior pectoral fascia, and used, for example toelevate the nipple during augmentation, capsulectomy, or lipoplastyreductions. In the face and neck, the self-retaining sutures may be usedin face-lift, forehead lift, neck lift, brow lift, and eyelid liftprocedures. For example, the self-retaining sutures can be used inlateral canthopexy (lower eyelid suspension surgery) to fix eyelids thatdroop or sag, or extended from the scalp into the brow, nasolabialfolds, jowls, or central neck. During lift procedures, theself-retaining sutures can be used to displace redundant tissue, forexample, up into the hairline.

In other preferred embodiments, the self-retaining sutures may be usedin: obstetrics and gynecological procedures, such as myomectomy,hysterectomy, sacrocolpopexy, and hemostasis, anastomosis, abdominalclosure, laparoscopic procedures, partial nephrectomy, and tendon andligament repair.

In still other embodiments, the sutures may be incorporated as part of adevice. Exemplary devices include, but are not limited to braidedsuture, hybrid suture of monofilament and multifilament fibers, braid,ligature, knitted or woven mesh, knitted tube, monofilament mesh,multifilament mesh, patch, wound healing device, bandage, wounddressing, burn dressing, ulcer dressing, skin substitute, hemostat,tracheal reconstruction device, organ salvage device, dural substitute,dural patch, nerve regeneration or repair device, hernia repair device,hernia mesh, hernia plug, device for temporary wound or tissue support,tissue engineering scaffold, guided tissue repair/regeneration device,anti-adhesion membrane, adhesion barrier, tissue separation membrane,retention membrane, sling, device for pelvic floor reconstruction,urethral suspension device, device for treatment of urinaryincontinence, device for treatment of vesicoureteral reflux, bladderrepair device, sphincter muscle repair device, suture anchor, boneanchor, ligament repair device, ligament augmentation device, ligamentgraft, anterior cruciate ligament repair device, tendon repair device,tendon graft, tendon augmentation device, rotator cuff repair device,meniscus repair device, meniscus regeneration device, articularcartilage repair device, osteochondral repair device, spinal fusiondevice, stent, including coronary, cardiovascular, peripheral, ureteric,urethral, urology, gastroenterology, nasal, ocular, or neurology stentsand stent coatings, stent graft, cardiovascular patch, vascular closuredevice, intracardiac septal defect repair device, including but notlimited to atrial septal defect repair devices and PFO (patent foramenovale) closure devices, left atrial appendage (LAA) closure device,pericardial patch, vein valve, heart valve, vascular graft, myocardialregeneration device, periodontal mesh, guided tissue regenerationmembrane for periodontal tissue, embolization device, anastomosisdevice, cell seeded device, controlled release device, drug deliverydevice, plastic surgery device, breast lift device, mastopexy device,breast reconstruction device, breast augmentation device (includingdevices for use with breast implants), breast reduction device(including devices for removal, reshaping and reorienting breasttissue), devices for breast reconstruction following mastectomy with orwithout breast implants, facial reconstructive device, forehead liftdevice, brow lift device, eyelid lift device, face lift device,rhytidectomy device, thread lift device (to lift and support saggingareas of the face, brow and neck), rhinoplasty device, device for malaraugmentation, otoplasty device, neck lift device, mentoplasty device,cosmetic repair device, and device for facial scar revision.

EXAMPLES

The present invention will be further understood by reference to thefollowing non-limiting examples.

Example 1: Extrusion of High Strength P4HB Monofilament

Bulk P4HB resin in pellet form was dried to under 300 ppm water using arotary vane vacuum pump system. The dried resin was transferred to anextruder feed hopper with nitrogen purge to keep the pellets dry. Thepellets were gravity fed into a chilled feeder section and introducedinto the extruder barrel, which was 1.50 inches in diameter and fittedwith an extrusion screw with a 30:1 L/D ratio. The extruder barrelcontained 5 heating zones (or extrusion zones)—zones 1, 2, 3, 4 and 5,and was manufactured by American Kuhne. The heated and softened resinfrom the extruder was fed into a heated metering pump (melt pump) andfrom the melt pump the extruded resin was fed into the heated block andan eight-hole spinneret assembly. Processing profile ranges from 40° C.to 260° C. for temperatures, and 400 psi to 2000 psi for pressures, wereused. The molten filaments were water quenched and conveyed into athree-stage orientation, before winding of the monofilaments on spools.In the three-stage orientation, the filaments were stretched 7×. Testvalues for extruded and oriented high strength P4HB monofilament fiberare shown in Table 4.

TABLE 4 Mechanical Test Data for High Strength P4HB Monofilament FiberFiber USP Diameter, Tensile Strength, Break Young's Size μm KgfElongation Modulus, GPa 3/0* 286 6.9 25% 1.8 2 584 26.1 28% 1.3 *exampleis oversized

Comparative Example 1: Extrusion of Medium Strength P4HB Monofilament

Bulk P4HB resin in pellet form was dried to under 300 ppm water using arotary vane vacuum pump system. The dried resin was transferred to anextruder feed hopper with nitrogen purge to keep the pellets dry. Thepellets were gravity fed into a chilled feeder section and introducedinto the extruder barrel, which was 1.50 inches in diameter and fittedwith an extrusion screw with a 30:1 L/D ratio. The extruder barrelcontained 5 heating zones (or extrusion zones)—zones 1, 2, 3, 4 and 5,and was manufactured by American Kuhne. The heated and softened resinfrom the extruder was fed into a heated metering pump (melt pump) andfrom the melt pump the extruded resin was fed into the heated block andan eight-hole spinneret assembly. Processing profile ranges from 40° C.to 260° C. for temperatures, and 400 psi to 2000 psi for pressures, wereused. The molten filaments were water quenched and conveyed into athree-stage orientation, with inline relaxation, before winding of themonofilaments on spools. In the three-stage orientation, the filamentswere stretched 7× then relaxed to 6.5×. Test values for extruded andoriented medium strength P4HB monofilament fiber are shown in Table 5.

TABLE 5 Mechanical Test Data for Medium Strength P4HB Monofilament FiberYoung's Fiber USP Diameter, Tensile Break Modulus, Size μm Strength, KgfElongation GPa 0* 440 10.9 54% 0.75 2/0* 352 6.4 57% 0.72 3/0* 281 4.457% 0.79 *example is oversized

Example 2: Preparation of an Oversized Size 3/0 High Strength P4HBSelf-Retaining Suture Meeting USP for Knot Strength

A high strength oversized size 3/0 poly-4-hydroxybutyrate monofilament,with a diameter of 286 μm, tensile strength of 6.9 Kgf, elongation tobreak of 25%, and a Young's Modulus of 1.8 GPa, was mechanically cut toform a self-retaining suture. The monofilament was cut using an angle of21.8 degrees measured relative to the longitudinal axis of themonofilament fiber (as shown in FIG. 1), and the depth of the cut(measured perpendicular to the longitudinal axis of the monofilamentfiber) was 120 μm. The length of the cut was 300 μm. The cuts werespaced at a distance of 300 μm apart with each successive cut offsetfrom the prior cut at an angle of 120 degrees around the circumferenceof the fiber. The density of cuts was 33.3 per cm of monofilamentlength. After cutting, the self-retaining monofilament fiber had atensile strength of 2.5 Kgf, elongation to break of 22%, and a Young'sModulus of 1.8 GPa. Notably, the tensile strength of the self-retainingsuture was 41% higher than the minimum USP knot strength of 1.77 Kgfrequired for a size 3/0 suture.

Comparative Example 2: Preparation of an Oversized Size 3/0 MediumStrength P4HB Self-Retaining Suture not Meeting USP for Knot Strength

A medium strength oversized size 3/0 poly-4-hydroxybutyratemonofilament, with a diameter of 281 μm, tensile strength of 4.4 Kgf,elongation to break of 57%, and a Young's Modulus of 0.79 GPa, wasmechanically cut to form a self-retaining suture. The monofilament wascut as listed in the above example 2. After placement of the retainers,the self-retaining monofilament suture had a tensile strength of 1.6Kgf, elongation to break of 28%, and a Young's Modulus of 0.79 GPa.Notably, the tensile strength of the barbed suture was 9.6% lower thanthe minimum USP knot strength of 1.77 Kgf required for a size 3/0suture.

Example 3: Preparation of a Size 2 High Strength P4HB Self-RetainingSuture Meeting USP for Knot Strength

A high strength size 2 poly-4-hydroxybutyrate monofilament, with adiameter of 584 μm, tensile strength of 26.1 Kgf, elongation to break of28%, and a Young's Modulus of 1.3 GPa, was mechanically cut to form aself-retaining suture. The monofilament was cut using an angle of 21degrees measured relative to the longitudinal axis of the monofilamentfiber (see FIG. 1), and the depth of the cut (measured perpendicular tothe longitudinal axis of the monofilament fiber) was 230 μm. The lengthof the cut was 600 μm. The cuts were spaced at a distance of 600 μmapart with each successive cut offset from the prior cut at an angle of120 degrees around the circumference of the fiber. The density of cutswas 16.6 per cm of monofilament. After placement of the retainers, theself-retaining monofilament suture had a tensile strength of 7.7 Kgf,elongation to break of 27%, and a Young's Modulus of 1.3 GPa. Notably,the tensile strength of the self-retaining suture was 21% higher thanthe minimum USP knot strength of 6.35 Kgf required for a size 2 suture.

Comparative Example 4: Preparation of an Oversized Size 0 MediumStrength P4HB Self-Retaining Suture not Meeting USP for Knot Strength

A medium strength oversized size 0 poly-4-hydroxybutyrate monofilament,with a diameter of 440 μm, tensile strength of 10.9 Kgf, elongation tobreak of 54%, and a Young's Modulus of 0.75 GPa, was mechanically cut toform a self-retaining suture. The monofilament was cut using an angle of23.7 degrees measured relative to the longitudinal axis of themonofilament fiber (see FIG. 1), and the depth of the cut (measuredperpendicular to the longitudinal axis of the monofilament fiber) was176 μm. The length of the cut was 400 μm. The cuts were spaced at adistance of 500 μm apart with each successive cut offset from the priorcut at an angle of 120 degrees around the circumference of the fiber.The density of cuts was 20 per cm of monofilament. After placement ofthe retainers, the self-retaining monofilament suture had a tensilestrength of 3.2 Kgf, elongation to break of 31%, and a Young's Modulusof 0.64 GPa. Notably, the tensile strength of the self-retaining suturewas 17.9% lower than the minimum USP knot strength of 3.9 Kgf requiredfor a size 0 suture.

Comparative Example 5: Preparation of an Oversized Size 2/0 MediumStrength P4HB Self-Retaining Suture not Meeting USP for Knot Strength

A medium strength oversized size 2/0 poly-4-hydroxybutyratemonofilament, with a diameter of 352 μm, tensile strength of 6.4 Kgf,elongation to break of 57%, and a Young's Modulus of 0.72 GPa, wasmechanically cut to form a self-retaining suture. The monofilament wascut using an angle of 22.4 degrees measured relative to the longitudinalaxis of the monofilament fiber, and the depth of the cut (measuredperpendicular to the longitudinal axis of the monofilament fiber) was140 μm. The length of the cut was 340 μm. The cuts were spaced at adistance of 350 μm apart with each successive cut offset from the priorcut at an angle of 120 degrees around the circumference of the fiber.The density of cuts was 28 per cm of monofilament. After placement ofthe retainers, the self-retaining monofilament fiber had a tensilestrength of 2.4 Kgf, elongation to break of 31%, and a Young's Modulusof 0.79 GPa. Notably, the tensile strength of the self-retaining suturewas 10% lower than the minimum USP knot strength of 2.68 Kgf requiredfor a size 2/0 suture.

Modifications and variations of the self-retaining monofilament suturesand methods of making and using described herein are intended to comewithin the scope of the appended claims. All references cited herein arespecifically incorporated by reference.

We claim:
 1. An absorbable self-retaining suture made from amonofilament fiber, wherein the monofilament fiber comprises asheath-core structure, wherein the core structure comprises the samepolymer as the sheath, and the core and sheath are oriented, wherein thefiber has been stretched at least 6 times its original length withoutsubsequent relaxation of the fiber, wherein the sheath and the core haveindentation hardness, and the indentation hardness of the sheath ishigher than the indentation hardness of the core, and wherein theself-retaining suture minimum straight pull tensile strength is selectedfrom the group consisting of (i) 0.25 Kgf when the average suturediameter is between 0.070 and 0.099 mm; (ii) 0.68 Kgf when the averagesuture diameter is between 0.10 and 0.149 mm; (iii) 0.95 Kgf when theaverage suture diameter is between 0.15 and 0.199 mm; (iv) 1.77 Kgf whenthe average suture diameter is between 0.20 and 0.249 mm; (v) 2.68 Kgfwhen the average suture diameter is between 0.30 and 0.339 mm; (vi) 3.90Kgf when the average suture diameter is between 0.35 and 0.399 mm; (vii)5.08 Kgf when the average suture diameter is between 0.40 and 0.499 mm;(viii) 6.35 Kgf when the average suture diameter is between 0.50 and0.599 mm; and (ix) 7.29 Kgf when the average suture diameter is between0.60 and 0.699 mm.
 2. The absorbable self-retaining suture of claim 1,wherein the minimum straight pull tensile strength of the self-retainingsuture is selected from the group consisting of: (i) 0.25 Kgf when theaverage suture diameter is between 0.070 and 0.149 mm; (ii) 0.68 Kgfwhen the average suture diameter is between 0.10 and 0.199 mm; (iii)0.95 Kgf when the average suture diameter is between 0.15 and 0.249 mm;(iv) 1.77 Kgf when the average suture diameter is between 0.20 and 0.349mm; (v) 2.68 Kgf when the average suture diameter is between 0.30 and0.439 mm; (vi) 3.90 Kgf when the average suture diameter is between 0.35and 0.499 mm; (vii) 5.08 Kgf when the average suture diameter is between0.40 and 0.599 mm; (viii) 6.35 Kgf when the average suture diameter isbetween 0.50 and 0.699 mm; and (ix) 7.29 Kgf when the average suturediameter is between 0.60 and 0.799 mm.
 3. The self-retaining sutures ofclaim 1 made from a monofilament fiber having a characteristic selectedfrom the group consisting of: (a) a monofilament fiber that has beenstretched at least 6 times its original length without subsequentrelaxation of the fiber; (b) a straight pull tensile strength that is atleast two times that of the self-retaining suture; and (c) amonofilament fiber that has been cut through up to 40% of its diameter.4. The monofilament fiber of claim 3 wherein the fiber has a Young'smodulus greater than 860 MPa.
 5. The self-retaining sutures of claim 3wherein the sheath comprises a surface, wherein the surface of thesheath of the self-retaining suture has an average indentation hardnessof at least 0.07 GPa.
 6. The self-retaining sutures of claim 3 whereinthe core of the self-retaining suture has an indentation hardness ofless than 0.07 GPa.
 7. The self-retaining sutures of claim 1 comprisinga monofilament fiber and retainers, wherein the retainers are cut,stamped, machined, molded or welded.
 8. The self-retaining sutures ofclaim 1 wherein the monofilament has cut at an angle of less than 60degrees, wherein the angle is measured relative to the longitudinal axisof the monofilament fiber.
 9. The self-retaining sutures of claim 8wherein the cuts are spaced at a distance of at least half the diameterof the monofilament fiber, offset from one another, placed in a helicalpattern, overlapping, ordered, staggered, random unidirectionalbidirectional or combinations thereof along the length of theself-retaining suture.
 10. The self-retaining sutures of claim 8 whereinthe length of the cut to make the retainers is between one-quarter totwice the diameter of the monofilament fiber.
 11. The self-retainingsutures of claim 1 wherein the sutures further comprise one or moreneedles, a looped end, or a needle on one end and a loop at the otherend.
 12. The self-retaining sutures of claim 1 wherein the suturescontain less than 20 endotoxin units (EU) per suture.
 13. Theself-retaining sutures of claim 1 wherein the sutures have beensterilized by ethylene oxide, electron beam irradiation, orgamma-irradiation.
 14. The self-retaining sutures of claim 1 furthercomprising a coating selected from the group consisting of a wax,natural polymer, synthetic polymer, resorbable polymer or combinationsthereof, or an additive selected from the group consisting ofplasticizers, nucleants, compatibilizers, porogens, radiolabelledsubstances, imaging agents, radiopaque markers, contrast agents, dyes,and bioactive agents.
 15. The self-retaining sutures of claim 1 whereinthe suture comprises a blend of an absorbable polymer with a naturalpolymer, synthetic polymer, or second absorbable polymer.
 16. Theself-retaining sutures of claim 15 wherein the second absorbable polymercomprises a monomer selected from the group consisting of glycolic acid,lactic acid, 1,4-dioxanone, trimethylene carbonate or ε-caprolactone.17. The self-retaining sutures of claim 1 wherein (a) the core structureand the sheath structure comprise suture comprisespoly-4-hydroxybutyrate homopolymer, or (b) the core structure and thesheath structure comprise a copolymer of poly-4-hydroxybutyrate.
 18. Theself-retaining suture of claim 17 wherein the weight average molecularweight of the poly-4-hydroxybutyrate or copolymer thereof is between 50kD and 1,200 kD.
 19. The self-retaining sutures of claim 1 wherein thesuture is a component of a device selected from the group consisting ofa braided suture, hybrid suture of monofilament and multifilamentfibers, braid, ligature, knitted or woven mesh, knitted tube,monofilament mesh, multifilament mesh, patch, wound healing device,bandage, wound dressing, burn dressing, ulcer dressing, skin substitute,hemostat, tracheal reconstruction device, organ salvage device, duralsubstitute, dural patch, nerve regeneration or repair device, herniarepair device, hernia mesh, hernia plug, device for temporary wound ortissue support, tissue engineering scaffold, guided tissuerepair/regeneration device, anti-adhesion membrane, adhesion barrier,tissue separation membrane, retention membrane, sling, device for pelvicfloor reconstruction, urethral suspension device, device for treatmentof urinary incontinence, device for treatment of vesicoureteral reflux,bladder repair device, sphincter muscle repair device, suture anchor,bone anchor, ligament repair device, ligament augmentation device,ligament graft, anterior cruciate ligament repair device, tendon repairdevice, tendon graft, tendon augmentation device, rotator cuff repairdevice, meniscus repair device, meniscus regeneration device, articularcartilage repair device, osteochondral repair device, spinal fusiondevice, stent, including coronary, cardiovascular, peripheral, ureteric,urethral, urology, gastroenterology, nasal, ocular, or neurology stentsand stent coatings, stent graft, cardiovascular patch, vascular closuredevice, intracardiac septal defect repair device, pericardial patch,vein valve, heart valve, vascular graft, myocardial regeneration device,periodontal mesh, guided tissue regeneration membrane for periodontaltissue, embolization device, anastomosis device, cell seeded device,controlled release device, drug delivery device, plastic surgery device,breast lift device, mastopexy device, breast reconstruction device,breast augmentation device, breast reduction, reshaping or reorientingdevice, devices for breast reconstruction following mastectomy with orwithout breast implants, facial reconstructive device, forehead liftdevice, brow lift device, eyelid lift device, face lift device,rhytidectomy device, thread lift device to lift and support saggingareas of the face, brow and neck, rhinoplasty device, device for malaraugmentation, otoplasty device, neck lift device, mentoplasty device,cosmetic repair device, and device for facial scar revision.
 20. Amethod for preparing the self-retaining sutures of claim 1 comprising:(a) spinning and orienting a monofilament fiber ofpoly-4-hydroxybutyrate or copolymer thereof wherein the average surfaceindentation hardness is at least 0.07 GPa; and (b) inserting retainersin the monofilament fiber to form self-retaining sutures, wherein thestraight pull tensile strength of the self-retaining suture is equal toor greater than the average minimum knot-pull tensile strength standardset by the USP for a suture of corresponding size.
 21. The method ofclaim 20 wherein the oriented monofilament fiber has a Young's modulusgreater than 860 MPa.
 22. The method of claim 20 wherein theself-retaining suture comprises one or more of the following: (i) adistance between any two retainers of 0-25 mm, (ii) a length of anyretainer between 0.01-10 mm, (iii) a retainer placed at an angle between5 and 60 degrees, wherein the angle is measured relative to thelongitudinal axis of the monofilament fiber, (iv) a retainer placed witha depth in the monofilament fiber of between 1 and 350 μm, (v) aretainer placed with a depth in the monofilament fiber of up to 40% ofthe diameter of the monofilament fiber (vi) retainers are positioned inordered, random, spiral, staggered, or overlapping configurations and(vii) the self-retaining suture further comprises a needle at one end orneedles at both ends of the suture fiber.
 23. The method of making theself-retaining sutures of claim 20 comprising: (i) drying bulk P4HBresin in pellet form until it has a water content of less than 300 ppmusing a rotary vane vacuum pump system, (ii) transferring the driedpellets to the feed hopper of the extruder fitted with a dry nitrogenpurge to keep the pellets dry, (iii) gravity feeding the P4HB pelletsinto a chilled feeder section, introducing the pellets into the extruderbarrel, feeding the heated and softened resin into a heated meteringpump (melt pump), and from the metering pump feeding the resin into aheated block and an eight-hole spinneret assembly, using a processingprofile of 40° C. to 260° C. for temperatures, and 400 psi to 2,000 psifor pressures, (iv) water quenching the molten P4HB monofilaments, and(v) conveying the quenched filaments into a multi-stage orientationline, and stretching of at least 6×, before winding the high strengthP4HB monofilament fiber on spools.
 24. A method of using theself-retaining suture of claim 1 comprising implanting the suture in thebody.
 25. The method of claim 24 wherein the self-retaining suture isused in obstetrics and gynecological surgery, myomectomy, hysterectomy,sacrolpopexy, cesarean delivery, orthopedic surgery, ligament and tendonrepair, wound closure, reduction of wide scar reduction, wound hernias,plastic surgery, lift procedures, mastopexy, breast reconstruction,breast augmentation, breast lift, elevation of the nipple, face-lift,forehead lift, neck lift, brow lift, eyelid lift, lateral canthopexy,hemostasis, cardiovascular surgery, anastomosis, abdominal closure,laparoscopic procedures, and partial nephrectomy.
 26. A monofilamentfiber of poly-4-hydroxybutyrate or copolymer thereof comprising asheath-core structure, wherein the monofilament has a Young's modulusgreater than 860 MPa, wherein (a) the core structure and the sheathstructure comprise poly-4-hydroxybutyrate homopolymer, or (b) the corestructure and the sheath structure comprise or a copolymer ofpoly-4-hydroxybutyrate, wherein the fiber has been stretched at least 6times its original length without subsequent relaxation of the fiber,wherein the sheath and the core have indentation hardness, and theindentation hardness of the sheath is higher than the indentationhardness of the core.
 27. The monofilament fiber of claim 26 wherein themonofilament fiber comprises a surface, wherein the surface of themonofilament fiber has an average indentation hardness of at least 0.07GPa.
 28. The monofilament fiber of claim 26, wherein the core of theself-retaining suture has an indentation hardness of less than 0.07 GPa.29. The monofilament fiber of claim 26 wherein the fiber has beenstretched at least 6.6 times its original length without subsequentrelaxation of the fiber.
 30. A medical device comprising themonofilament fiber of claim 24 wherein the device is selected from thegroup consisting of a suture, braided suture, hybrid suture ofmonofilament and multifilament fibers, braid, ligature, knitted or wovenmesh, knitted tube, monofilament mesh, multifilament mesh, patch, woundhealing device, bandage, wound dressing, burn dressing, ulcer dressing,skin substitute, hemostat, tracheal reconstruction device, organ salvagedevice, dural substitute, dural patch, nerve regeneration or repairdevice, hernia repair device, hernia mesh, hernia plug, device fortemporary wound or tissue support, tissue engineering scaffold, guidedtissue repair/regeneration device, anti-adhesion membrane, adhesionbarrier, tissue separation membrane, retention membrane, sling, devicefor pelvic floor reconstruction, urethral suspension device, device fortreatment of urinary incontinence, device for treatment ofvesicoureteral reflux, bladder repair device, sphincter muscle repairdevice, suture anchor, bone anchor, ligament repair device, ligamentaugmentation device, ligament graft, anterior cruciate ligament repairdevice, tendon repair device, tendon graft, tendon augmentation device,rotator cuff repair device, meniscus repair device, meniscusregeneration device, articular cartilage repair device, osteochondralrepair device, spinal fusion device, stent, including coronary,cardiovascular, peripheral, ureteric, urethral, urology,gastroenterology, nasal, ocular, or neurology stents and stent coatings,stent graft, cardiovascular patch, vascular closure device, intracardiacseptal defect repair device, left atrial appendage (LAA) closure device,pericardial patch, vein valve, heart valve, vascular graft, myocardialregeneration device, periodontal mesh, guided tissue regenerationmembrane for periodontal tissue, embolization device, anastomosisdevice, cell seeded device, controlled release device, drug deliverydevice, plastic surgery device, breast lift device, mastopexy device,breast reconstruction device, breast augmentation device, breastreduction, reshaping or reorienting device, devices for breastreconstruction following mastectomy with or without breast implants,facial reconstructive device, forehead lift device, brow lift device,eyelid lift device, face lift device, rhytidectomy device, thread liftdevice to lift and support sagging areas of the face, brow and neck,rhinoplasty device, device for malar augmentation, otoplasty device,neck lift device, mentoplasty device, cosmetic repair device, and devicefor facial scar revision.